Lactams Macrolactams

J. A. Macrolactamization via Pd Jt-allyl alkylation. Preparation of CGS25155 a 10-mem-bered lactam neutral endopeptidase 24.11 inhibitor. J. Org. Chem. 1995, 60, 6595-6598. Bonnet, B. Pie, G. Duhamel, L. Competition between metalation and halogen—lithium exchange in halovinylic acetals. Synlett 1996, 221-224. 

The method is useful for synthesis of five-, six- and seven-membered lactams, but not of P-lactams or macrolactams. The bridged lactam 2 was obtained from 1 in 77% yield by reaction with di-n-butyltin oxide. 

An acyl chloride was used in the synthesis of the spermidine alkaloid cannabisativine (162) by Natsume and coworkers [92]. As shown in Scheme 53, the precursor 160 was hydrolyzed with Ba(OH)2 and the resulting amino acid was directly converted to acyl chloride HCl salt, a cold solution of which was added dropwise to a potassium carbonate suspension in acetonitrile to achieve the lactam closure. Deprotection of the methoxymethyl groups with acid afforded macrolactam 161 in 43% yield from 160. 

Macrolactamization Carboxylic esters containing polyamine units undergo cyclization facilitated by preorganization with Sb(OEt)j. Based on the ready preparation of a phenyl-substituted 17-membered lactam by this method in 90% yield, synthesis of several spermine alkaloids (verbacine, verbaskine, and verbascenine) is achieved in a straightforward manner. 

Lactamization. A key step in the first total synthesis of a maytansenoid, macrolactams with antitumor activity, involved cyclization of the amino acid 1. This reaction was effected by conversion of the acid into the soluble tetra-n-butylammonium salt and addition of this salt to a solution of mesitylenesulfonyl chloride and diisopropylethylamine in benzene (3 hours, 35°). The lactam 2 was... 

The macrolactamization strategy for the closure of the 14-membered D ring, previously developed from model structures, was applied to the dia-zatricychc acid 96 to afford tetracyclic lactam 97. Acid 96, which already incorporates the required functionalized 11-carbon chain at C-9, was prepared in four steps from the enantiopure alcohol 64 oxidation of the C-3... 

Thus, treatment of the model ketone 114 with the ylide, generated from 115 under strictly anhydrous conditions, stereoselectively installed the exocyclic double bond (Z/E, 10 1 ratio), leading to the diene 116. After removal of the tosyl protecting group, alkaline hydrolysis followed by macrolactamization of the resulting crude amino acid provided the tricyclic lactam 117. 

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